Starvation in the Midst of Plenty? The Role of Hypoxia in Progression
Authors: T. Tanaka, T. Miyata, R. Inagi, T. Fujita, M. Nangaku
Journal: Journal of the American Society of Nephrology (2005)

The kidney, which receives 20% of the cardiac output, is at first glance an extremely unlikely candidate for a pathogenetic role of hypoxia, at least as far as the renal cortex is concerned. While the deleterious roles of hypertension and proteinuria in progression were suspected and accepted relatively early, suspicion of a pathogenetic role of hypoxia has been slow in coming. With the introduction of a renal biopsy technique, it was noted early on that tubulointerstitial lesions were more closely related to loss of renal function than glomerular lesions (1–3). To explain this initially puzzling finding, Bohle proposed that interstitial lesions are associated with loss of peritubular capillaries, thus causing hypoxia (3,4). To put it mildly, this idea was not enthusiastically received because of the presumed rich oxygen supply of the renal cortex. However, the important functional implications of the loss of peritubular capillaries have recently been well documented (5,6). It is worth reminding that the renal community had to accept the equally surprising finding that the sensor detecting oxygen deficiency and stimulating synthesis of erythropoietin was, of all places, located in the peritubular space of the renal cortex, which had been thought to have an abundant supply of oxygen. Pursuing the proposal of Bohle, Leon Fine put forward the hypothesis that hypoxia is the consequence of the depletion of peritubular capillaries and plays an important role as progression promoter (7,8). This hypothesis found support by in vitro work (8,9), which documented that a low pO2 stimulated collagen production by interstitial fibroblasts. Although low pO2 values were indeed measured in the renal interstitium (10), methodological problems remained and the reported results were conflicting (11). The smoking gun, i.e., evidence of very low interstitial pO2 values in renal damage models and documentation of a topographical relationship between regions of hypoxia and of fibrogenesis, were lacking. The work of Tanaka et al. has now achieved a breakthrough and put hypoxia squarely back on the map. The investigators reasoned that the chemical tools used hitherto for this purpose, e.g., nitroimidazoles, lacked sensitivity and resolution with respect to the time course. Therefore they developed a novel transgenic rat model, taking advantage of the hypoxia-responsive element (HRE) of the rat vascular endothelial growth factor (VEGF) gene to create a HRE-driven tagged luciferase construct. Hypoxia sensing by this construct was validated and quantitated by in vitro studies, and induction of the transgene by hypoxia was proven using cobalt chloride as a surrogate stimulus of hypoxia. Not unexpectedly, even under normoxic conditions the construct indicated the presence of hypoxia in the renal medulla. Cobalt increased the hypoxia signal, however, in tubular cells, glomerular epithelial cells, and interstitial cells. The authors then went one step further and examined whether the construct indicated hypoxia in rats with chronic progressive renal damage. To exclude model-specific artifacts, they wisely studied two different models: The puromycin aminonucleoside model of nephrotic syndrome and the remnant kidney model. The transgene construct was upregulated, although to a different degree, in both models. The degree of impairment of renal function (e.g., blood urea nitrogen levels), as well as the extent of tubulointerstitial injury, were clearly correlated to the intensity of hypoxia indicated by the transgene construct. An impressive regional correlation was noted between areas of hypoxia and areas of macrophage accumulation, apoptosis, and cell proliferation, indicated by proliferating cell nuclear antigen (PCNA). The peritubular capillaries showed signs of damage recognized from the previous experiments of Kang et al. (5), suggesting that impaired tubulointerstitial blood flow, presumably caused by a deficit of VEGF and nitric oxide (NO) (6), had created the regional foci of hypoxia postulated by Bohle (3). The hypothesis that hypoxia is at least one of the factors triggering and perpetuating progression is further supported by previous findings that hypoxia even precedes evidence of renal damage (12,13). Oxygen-sensing in the kidney is obviously mediated by hypoxia-inducible factor(s)-1 and -2 (HIF-1 and HIF-2) as recently documented by Rosenberger et al. (14,15). HIF is involved not only in the control of the synthesis of erythropoietin (EPO), but more generally triggers metabolic and structural responses to hypoxia such as stimulation of glycolysis, angiogenesis, etc. in different organs (16). What are the implications of the findings of Tanaka et al.? Because hypoxia sensing is such a central mechanism, the implications of the findings are presumably far-reaching in situations of progressive renal damage. Renal hypoxia is obviously of moderate intensity and fails to induce hypoxic necroses, but nevertheless it may become a target for therapeutic intervention in the future. So far, tantalizing observations from the Irbesartan Diabetic Nephropathy Trial (IDNT) (unpublished) and the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial (17) indicate that a low hemoglobin value is a predictor of more rapid progression of renal failure. Whether this is due to hypoxia induced by anemia or a result of EPO deficiency is currently unknown. We shall soon have the results of ongoing trials, however, to clarify at least whether correction of anemia by EPO attenuates the rate of progression. Possibly the beneficial effects of other interventions as well are mediated by modulating hypoxia, at least in part (18). At any rate it is safe to predict that the communication of Tanaka et al. will spawn further experimental and clinical studies to clarify the exact role of hypoxia as a progression promoter.